This invention relates to pyrimidine derivatives and, more particularly, to a selected group of 2,4-diamino-6-methyl-5-(halophenylazo) pyrimidine compounds having a high level of activity as folic acid antagonists.
Folic acid, which is a naturally occurring compound generally contained in the liver and kidneys, is a required factor for certain metabolic reactions and for the growth of certain microorganisms. Drugs which act to prevent the utilization of folic acid, for example, by a competitive binding action, are known as "folic acid antagonists" or "antifolates." This class of drugs has been successfully used for suppressing immune response and in the treatment of various bacterial diseases, protozoal diseases, neoplastic diseases and psoriasis. Some of the more commonly employed folic acid antagonists include, for example, trimethoprim, which is used either alone or in combination with sulfonamides for various bacterial diseases; pyrimethamine, which is used for the treatment of plasmodial diseases; cycloguanilhydrochloride, which is most frequently primarily considered as an antimalarial agent; aminopterine, which has been used for the treatment of various forms of cancer; and methotrexate, which is used for suppressing immune response, for the treatment of psoriasis, and for various kinds of tumors, particularly for the treatment of cancer in children.
In addition to the above-described folic acid antagonists which have been used clinically, a number of substituted 5-arylazo pyrimidine compounds have previously been investigated for their antifolic activity. One of these compounds, 2,4-diamino-6-methyl-5-(phenylazo) pyrimidine, was involved in a limited study reported by Chatterjee et al (Journal of Medicinal Chemistry, 1971, volume 14, No. 12, pages 1237-1238) to determine the effect of various substituents in the 6-position of the pyrimidine ring of 2,4-diamino-5-(phenylazo) pyrimidine compounds on their inhibitory activity toward dihydrofolate reductase. Chatterjee et al found that introduction of the 6-methyl group resulted in increased activity in comparison with the corresponding 6-unsubstituted and 6-amino compounds, but not to the same extent as did introduction of the 6-hydroxy group. While Chatterjee et al also found that the activity of the 6-hydroxy compound could be further increased by a 6-fold amount by introducing an o-ethyl substituent in the phenyl ring, no similar or any other modification of the 6-methyl compound was reported.